The subject of the invention is novel 7-substituted 3-carboxy-oxadiazino-quinolone derivatives, their preparation and their application as anti-bacterials.
7-substituted 3-carboxy-oxadiazino-quinolone derivatives have been described in numerous patents, applications or publications and there may be cited for example EP 0259804, EP 0343524, EP 0688772, U.S. Pat. Nos. 4,990,517, 5,480,879, 5,679,675, or also J. Med. Chem 1996, 39, 3070-3088, J. Med. Chem 2002, 45, 5564-5575, or J. Med. Chem 2004, 47, 2097-2109.
A subject of the invention is the compounds of formula (I):
in which                either R1 represents:        
H, OH, NH2, —(CH2)m—NRaRb in which m=0.1 or 2,
Ra and Rb are identical or different and represent H, linear, branched or cyclic (C1-C6) alkyl, (C3-C6) cycloalkyl-(C1-C6)-alkyl;
or also represent Rc, S(O)2Rc, C(O)Rc, S(O)2Rd or C(O)Rd;
or Ra and Rb form together with the nitrogen atom, an Rc radical;
Rc represents a saturated, unsaturated or aromatic 5- to 6-member ring containing 1 to 4 heteroatoms chosen from N, O and S, optionally substituted by 1 to 3 (C1-C6) alkyl radicals, said ring being linked, if appropriate, to the nitrogen atom of NRaRb by a nitrogen atom or a carbon atom;
Rd represents a linear or branched (C1-C6) alkyl or (C3-C6) cyclic alkyl radical, optionally substituted by 1 to 4 halogens;
or R1 represents Rc or CHReRc or CHReRd;
Rc and Rd are as defined above, Re represents H, OH, NH2, NH—(C1-C6)-alk or N—(C1-C6) -alk2, or NH—(C1—C7)-acyl or NHRc, Rc being as defined above;
R2 represents:
H, (CH2)m—NRaRb, Rc, CHReRc or CHReRd,
Ra, Rb, Rc, Rd and Re are as defined above;
and R′2 represents H;
it being understood that R1 and R2 cannot at the same time be H or that R1 and R2 or R2 and R1 cannot be one (CH2)m—NRaRb or Rc or H and the other one OH, or one H and the other one NH2, or one H and the other one (CH2)m—NRaRb in which Ra and Rb represent H or (C1-C6) alkyl or C(O)Rd, in which Rd represents an unsubstituted linear or branched (C1-C6) alkyl or (C3-C6) cyclic alkyl radical;                or R1 has the above definition except H and R2 and R′2 together represent gem (C1-C6) dialkyl or (C1-C6) alkyl-oxime, or R2 and R′2 represent respectively Rc or Rd and OH, NH2, NHRc or NHRf, Rc and Rd being as defined above and Rf being a (C1-C7) acyl radical;        or R1 represents H and R2 and R′2 together represent (C1-C6) alkyl-oxime or one represents Rc and the other one represents OH, NH2, NHRc or NHRf, Rc and Rf being defined as above;        
n is 0 or 1;
R3 and R′3, identical or different, represent H or (C3-C6) alkyl optionally substituted by 1 to 3 halogens or R3 represents a (C1-C6) alkoxy carbonyl group and R′3 represents H;
R4 represents methyl optionally substituted by one to three halogens;
R5 represents H, (C1-C6) alkyl or (C7-C12) arylalkyl;
R6 represents H, fluorine, NO2, CF3 or CN;
in the form of mixtures of enantiomers or single enantiomers, as well as their addition salts with mineral and organic acids and their salts with mineral or organic bases.
The compounds of the invention have remarkable antibacterial properties which make them particularly indicated for use as medicaments in both human and veterinary medicine.
In general formula (I) and hereafter:
by linear or branched (C1-C6) alkyl radical is meant any possible radical and in particular methyl, ethyl, propyl or isopropyl, butyl, isobutyl or tert-butyl;
by cyclic (C1-C3) alkyl radical is meant cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;
by arylalkyl radical is meant preferably benzyl or phenethyl;
by halogen is meant fluorine, chlorine, bromine or iodine, and preferably fluorine;
by (C1-C7) acyl radical is meant any possible radical and in particular acetyl propionyl, butyryl or benzoyl.
When Rc represents a saturated ring, this is for example a pyrrolidine, piperidine, piperazine or morpholine ring. When Rc represents an unsaturated or aromatic ring, it is for example a pyrrole, furane, thiophene, pyrazole, triazole, tetrazole, thiazole, isothiazole, thiadiazole, imidazole, isoxazole, furazane, pyridine, pyrazine, pirimidine or pyridazine ring. When Rc is substituted, it is in particular by one or, if appropriate, two methyl radicals.
Among the acid salts of the products of formula (I), there may be cited, among others, of those formed with mineral acids, such as hydrochloric, hydrobromic, hydroiodic, sulphuric or phosphoric acid or with organic acids such as formic, acetic, trifluoroacetic, propionic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic, aspartic, alkanesulphonic acids, such as methanesulphonic and ethanesulphonic acids, arylsulphonic acids such as benzenesulphonic and paratoluenesulphonic acids. Among the alkaline salts of the products of formula (I), there may be cited, among others, those formed with mineral alkalis such as, for example, sodium, potassium, lithium, calcium, magnesium or ammonium hydroxide or organic bases such as, for example, methylamine, propylamine, trimethylamine, diethylamine, triethylamine, N,N-dimethylethanolamine, tris(hydroxymethyl)aminomethane, ethanolamine, pyridine, piperidine, piperazine, picoline, dicyclohexylamine, morpholine, benzylamine, procaine, lysine, arginine, histidine, N-methylglucamine. A particular subject of the invention is compounds of formula (I) as defined above, in which R3 and R′3 represent H and R4 represents methyl, as well as those in which R6 represents fluorine. A further particular subject of the invention is the compounds of formula (I) in which one of the substituents R1 and R2 represents (CH2)m—NRaRb in which m is 0 or 1, Rc, CHReRc or CHReRd, and the other represents H. Among these, there may be cited more particularly those in which one of the substituents R1 and R2 represents (CH2)m—NRaRb in which m is 0, and the other represents H, and quite particularly among these latter:                those in which one of the substituents Ra or Rb represents a 5- or 6-member aromatic ring, containing 1 to 4 heteroatoms chosen from N, O and S, optionally substituted by 1 to 3 (C1-C6) alkyl radicals, said ring being linked, if appropriate, to the nitrogen atom of NRaRb by a nitrogen atom or a carbon atom, and the other represents H, and        those in which one of the substituents Ra or Rb represents a C(O)Rd radical and the other represents H.        
A further particular subject of the invention is compounds of formula (I) as defined above, in which one of the substituents R1 and R2 represents CHReRc or CHReRd and the other represents H. A further particular subject of the invention is compounds of formula (I) as defined above, in which R1 represents OH or NH2 and R2 and R′2 represent gem (C1-C6) dialkyl, as well as those in which R1 represents hydrogen or —(CH2)m—NRaRb and R2 and R′2 represent (C1-C6) alkyl oxime. The preferred compounds of formula (I) according to the invention are those in which n=0.
Among compounds of the invention, there may be cited the compounds described in the experimental part, in particular those whose names follow:    8-fluoro-3-methyl-6-oxo-9-[3-(pyrazine-2-ylaminomethyl)-pyrrolidine-1-yl]-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylic acid,    8-fluoro-3-methyl-6-oxo-9-[(3-pyrazine-2-ylamino)-pyrrolidine-1-yl]-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylic acid,    8-fluoro-3-methyl-6-oxo-9-[3-(1,3,4-thiadiazol-2-ylamino)-pyrrolidine-1-yl]-2,3-dihydro-6H-1-oxa-3,3 a-diaza-phenalene-5-carboxylic acid,    8-fluoro-3-methyl-6-oxo-9-[(S)-3-(thiazol-2-ylamino)-pyrrolidine-1-yl]-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylic acid,    8-fluoro-3methyl-6-oxo-9-[3-(2,2,2-trifluoro-acetylamino)-pyrrolidine-1-yl]-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylic acid,    8-fluoro-3-methyl-6-oxo-9-[(R)-3-(2,2,2-trifluoro-acetylamino)-pyrrolidine-1-yl]-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylic acid,    9-((R,S)-4-amino-3,3-dimethyl-pyrrolidine-1-yl)-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylic acid,    9-((R)-4-amino-3,3-dimethyl-pyrrolidine-1-yl)-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylic acid,    9-[3-(amino-thiazol-2-yl-methyl)-pyrrolidine-1-yl]-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylic acid,    8-fluoro-9-[3-(Z/E)-methoxyimino)-pyrrolidine-1-yl]-3-methyl-6-oxo-2,3-dihydro-6-H-1-oxa-3,3a-diaza-phenalene-5-carboxylic acid,    8-fluoro-9-[3-(aminomethyl)-4-methoxyimino-pyrrolidine-1-yl]-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylic acid,    8-fluoro-3-methyl-6-oxo-9-[(R)-3-(thiazol-2-ylamino)-pyrrolidine-1-yl]-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylic acid,    8-fluoro-3-methyl-6-oxo-9-[(S)-3-(2,2,2-trifluoro-acetylamino)-pyrrolidine-1-yl]-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylic acid,    9-((S)-4-amino-3,3-dimethyl-pyrrolidine-1-yl)-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1oxa-3,3a-diaza-phenalene-5-carboxylic acid,
as well as their salts.
The compounds of the invention can be prepared by a method characterized in that a compound of formula (II) is treated:
in which R3, R′3, R4 and R6 are as defined above and R′5 has the values of R5 defined above or represents another group protecting the carboxylic function, by a compound of formula (III):
in which R1, R2, R′2 and n are as previously defined, in the presence of a base, then, if appropriate, the protective groups present are eliminated.
The procedure is carried out preferably in a sealed chamber, in solution in the pyridine, at the reflux temperature of the latter. The base used is preferably a tertiary amine, for example triethylamine, N-methyl morpholine or also DBU. When R′5 represents a protective group, it can in particular be a (C1-C6) alkyl, a (C2-C6) alkenyl, or a (C7-C14) arylalkyl. After final elimination of the protective group R′5, the acid obtained can if desired be reesterified to form a compound in which R5 is different from hydrogen. The compounds of the invention in which R2 and R′2 represent (C1-C6) alkyl-oxime can also be prepared by a method characterized in that a compound of formula (IV) is treated:
by an alkoxylamine or a salt of the latter.The procedure is carried out for example by action of an alkoxylamine chloride, in the presence of a base, in particular an alkaline carbonate or bicarbonate, in solution in an alkanol or in an alkanol-tetrahydrofurane-water mixture.
The compound of formula (IV) can be prepared from the corresponding alcohol, for example by a Swem type oxidation reaction, in the presence of oxalyl chloride, dimethylsulphoxide and a base, for example an amine such as triethylamine. Certain compounds of formula (III) are known, even commercially available, or can be prepared by methods known to a person skilled in the art. Preparation methods are given below, as well as in the experimental part. The compound of formula (III) in which R1 or R2 represents a —CH2)m—NRaRb radical in which Ra and/or Rb represent Rc or Rd can be prepared from a compound of formula (V):
in which Pr represents a group protecting the nitrogen of the ring and m and n are as defined above, by action of a compound of formula (VI):Rc-Hal or Rd-Hal  (VI)in which Rc and Rd are defined as previously and Hal represents a halogen, in the presence of a strong base, followed by deprotection of the nitrogen of the ring.
The procedure is carried out for example in the presence of an alkaline alkoxide, in solution in a solvent such as toluene. Hal is preferably a chlorine or a bromine.
The compound of formula (III) in which R1 or R2 represents a —(CH2)m—NRaRb radical in which Ra or Rb or Ra and Rb represent Rc can also be prepared from a compound of formula (VII):
in which m, n and Pr are defined as previously, by action of a compound of formula (VIII):Rc—NHP or Rc—NH  (VIII)in which Rc and Pr are defined as previously, in the presence of triphenylphosphine and diethyldiazadicarboxylate, in tetrahydrofurane, followed by deprotection of the nitrogen atoms. The compound of formula (III) in which R1 or R2 represents a —(CH2)m—NraRb radical in which Ra or Rb or Ra and Rb represent C(O)Rc or C(O)Rd can be prepared from a compound of formula (V) as defined above, by action of a compound of formula (IX):Rc—COOH or Rd—COOH  (IX)by a peptide coupling reaction in the presence of EDCI/HOBt in solution in a solvent such as DMF,
or by action of a corresponding acid halide or its corresponding anhydride, in the presence of a base, for example an amine such as triethylamine, in a solvent such as dichloromethane, followed by deprotection of the nitrogen of the ring.
The compound of formula (III) in which R1 or R2 represents a (CH2)m—NRaRb radical in which Ra or Rb or Ra and Rb represent S(O)2Rc or S(O)2Rd can be prepared from a compound of formula (V) as defined above, by action of a corresponding alkylsulphonic acid anhydride, in the presence of a base, for example an amine such as triethylamine, in a solvent such as dichloromethane, followed by deprotection of the nitrogen of the ring. The compound of formula (III) in which R1 or R2 represents a —(CH2)m—NRaRb radical in which one of Ra and Rb represents H and the other represents an Rc radical of 4,5-dihydro-thiazol-2-yl type can be prepared from a compound of formula (V) as defined above,
by action of the thiocarbonylimidazole, in order to obtain the corresponding thiocyanate which is treated with 2-chloroethylamine, or its hydrochloride, in the presence of a base, for example triethylamine, followed by deprotection of the nitrogen of the ring.
The compound of formula (III) in which R1 or R2 represents a —(CH2)m—NRaRb radical in which Ra and Rb together form an Rc radical can be prepared either from a compound of formula (VI) as defined above, by action of a compound H—Rc, H being fixed to a nitrogen atom of the Rc ring, in the presence of diethylazadicarboxylate and triphenylphosphine in the THF, either from a reactive derivative of the hydroxy of the compound of formula (VI), in particular a mesylate, by action of the same H—Rc compound, in the presence of sodium hydride in DMF, followed by deprotection of the nitrogen of the ring. The compound of formula (III) in which R1 or R2 represents a —(CH2)m—NRaRb radical in which m is equal to 0 and Ra and Rb together form an Rc radical of [1.2,3]-triazol-1-yl type can also be prepared from a compound of formula (X):
in which Pr and n are defined as previously,by action of the bicyclo[2,2,1]hepta-2,5-diene, followed by deprotection of the nitrogen of the ring.
The compound of formula (III) in which R1 or R2 represents an Rc radical of 1H-tetrazole-5-yl type can also be prepared from a reagent derivative of the hydroxy of the compound of formula (VII), in particular a mesylate, by action of the tetrabutylammonium cyanide in acetonitrile, in order to obtain the corresponding cyanide derivative, which is treated with sodium azide in the presence of a base, for example an amine such as triethylamine, in a solvent such as toluene, followed by deprotection of the nitrogen of the ring. The compound of formula (III), if appropriate in protected form, in which R1 represents OH or NH2 and R2 and R′2 represent gem dialkyl can be prepared by methods known to a person skilled in the art and in particular by the method described by Di Cesare et al, J Med Chem 1992, 35, (22), 4205-13. The compound of formula (III), if appropriate in protected form, in which R1 represents H and R2 and R′2 represent respectively Rd and OH, NH2 or NHRf, can be prepared by methods known to a person skilled in the art and in particular by the method described by Britton et al, WO0644454, or by Matsumoto et al, U.S. Pat. No. 4,649,144, or by Giordanetto et al, WO0711284, or also by Hossain et al, WO04/5295.
The compound of formula (III), if appropriate in protected form, in which R1 represents H and R2 and R′2 represent respectively Rc and OH can be prepared from the corresponding keto compound, by action of an Rc-Hal compound, in particular Rc—Br, in the presence of a strong base, in particular butyl lithium, in solution in the tetrahydrofurane, followed if appropriate by deprotection of the nitrogen of the ring. The compound of formula (III) in protected form at the nitrogen of the ring, in which R1 represents CHReRc or CHReRd, Re being an OH, can be prepared from the corresponding 2-keto compound, by action of an ester-type compound of formula RcCOOalk or RdCOOalk, Rc and Rd being as defined above, in the presence of lithium diisopropylamide in THF, in order to obtain a compound of formula (XI):
in which Rc, Rd, n and Pr are as previously defined,which is reduced by potassium borohydride in methanol, in order to obtain a compound of formula (XII):
which is reduced by LiAlH4 in the presence of aluminium chloride in THF. The compound is then deprotected at the nitrogen of the ring. A method of this type is described in application WO2005/026154 and in the experimental part.
The compound of formula (III) in protected form, in which R1 represents CHReCc or CHReRd, Rc being an OH, can also be prepared from the compound of formula (XIII):
in which Pr and n are as previously defined,by action of oxalyl chloride in DMSO in the presence of a base such as triethylamine, in order to obtain a compound of formula (XIV):
in which n and Pr are as previously defined,which is treated with a compound of Rc-Hal or Rd-Hal type, Hal being in particular a bromine, in the presence of a base such as butyl lithium. The compound is then deprotected. A method of this type is described in application WO2005/026154 and further in the experimental part.
The compound of formula (III) in protected form, in which R1 represents CHReRc or CHReRd, Re being a NH2 or NHRf, can be prepared from the compound obtained above, the OH function of which is activated by action of methanesulphonyl chloride in the presence of a base, for example triethylamine, within dichloromethane, then treated with sodium azide in DMF, in order to obtain the compound of formula (XV):
which is reduced by hydrogen in the presence of palladium over carbon with an alkanol. The compound is isolated in protected form regarding the nitrogen of the ring. The compound is then deprotected. A method of this type is described in patent EP 1182202 and further in the experimental part.
Protection of the heterocyclic nitrogen and the amines is carried out in particular, according to circumstances, in the form of benzyle or trityle derivatives, in the form of carbamates, in particular allyl, benzyl, phenyl or tertbutyl, or also in the form of silyl derivatives such as dimethyl, trimethyl, triphenyl tertbutyl or also diphenyl tertbutyl-silyl derivatives. Deprotection is carried out, according to the nature of the protective group, by sodium or lithium in liquid ammonia, by hydrogenolysis or using soluble palladium 0 complexes, by action of an acid, or by action of tetrabutylammonium fluoride or strong bases such as sodium hydride or potassium tert-butylate. These reactions are well known to a person skilled in the art and examples are given hereafter in the experimental part. The compound of formula (II) is generally known and can be prepared by the methods described in U.S. Pat. No. 4,801,584.
The compound of formula (II) in which R3 and/or R′3 represent/s an alkyl radical optionally substituted by 1 to 3 halogens can be prepared from a compound of formula (II) in which R3 and R′3 represent a hydrogen, which is hot-treated with an alkaline aqueous base then neutralized, in order to obtain the compound of formula (XVI):
in which R4, R′5 and R6 are defined as above, which is treated in dioxane at boiling point by a compound of formula (XVII)
in which R3 and R′3 are defined as above.
The compound of formula (II) in which R4 represents a methyl radical substituted by 1 to 3 halogens can be prepared according to a method of the type described in U.S. Pat. No. 4,801,584. As stated above, the compounds of formula (I) can be in the form of enantiomers or mixtures of enantiomers essentially at position 9 of the ring. The compounds of formula (I) are obtained without racemization and as a result enantiomers can be obtained by using the corresponding enantiomer of the compound of formula (III) or (IV). The compounds according to the invention have remarkable antibacterial properties and these properties manifest themselves over a wide spectrum of gram (−) bacteria, but also a wide spectrum of gram (+). This balanced antibacterial activity distinguishes them from the similar compounds of the prior art, for example marbofloxacine or also ofloxacine, and means that they are particularly indicated for use as medicaments in human medicine, but also in veterinary medicine for which there is a need for compounds which are particularly active in relation to these bacteria. Thus the compounds are active in particular on gram (+) bacteria such as Streptococcus uberis or Staphylococcus aureus, but also Mycoplasma bovis or bovirhinis, or Clostridium perfringens or Enterococcus faecalis, while still being remarkably active on gram (−) bacteria such as Mannheimia haemolytica, Bordetella bronchiseptica, Escherichia coli or Pseudomonas aeruginosa. These properties make said products, as well as their salts with pharmaceutically acceptable acids and bases, suitable for use as medicaments in the treatment of conditions with susceptible germs and in particular those involving staphylococci, such as staphylococcal septicaemia, malignant staphylococcal infection of the face or skin, pyoderma, septic or suppurating sores, anthrax, phlegmon, erysipeles, primitive or post-influenzal acute staphylococcal infections, bronchial pneumonia, pulmonary suppurations.
These products can also be used as medicaments in the treatment of colibacilloses and associated infections, in Proteus, Klebsiella, Pseudomonas or also Salmonella infections and in other conditions caused by gram (−) bacteria. A further subject of the present invention is therefore, as medicaments and in particular antibiotic medicaments, the products of formula (I) as defined above as well as their salts with pharmaceutically acceptable acids and bases.
More particularly, a subject of the invention is, as medicaments, the preferred products of formula (I) mentioned above, in particular including the compounds whose names follow:    8-fluoro-3-methyl-6-oxo-9-[3-(pyrazine-2-ylaminomethyl)-pyrrolidine-1-yl]-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylic acid,    8-fluoro-3-methyl-6-oxo-9-(3-pyrazine-2-ylamino)-pyrrolidine-1-yl)-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylic acid,    8-fluoro-3-methyl-6-oxo-9-[3-(1,3,4-thiadiazol-2-ylamino)-pyrrolidine-1-yl]-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylic acid,    8-fluoro-3-methyl-6-oxo-9-[(S)-3-(thiazol-2-ylamino)-pyrrolidine-1-yl]-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylic acid,    8-fluoro-3methyl-6-oxo-9-(3-(2,2,2-trifluoro-acetylamino)-pyrrolidine-1-yl)-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylic acid,    8-fluoro-3-methyl-6-oxo-9-((R)-3-(2,2,2-trifluoro-acetylamino)-pyrrolidine-1-yl(-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylic acid,    9-((R,S)-4-amino-3,3-dimethyl-pyrrolidine-1-yl)-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylic acid,    9-((R)-4-amino-3,3-dimethyl-pyrrolidine-1-yl)-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylic acid,    9-(3-(amino-thiazol-2-yl]-methyl)-pyrrolidine-1-yl]-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylic acid,    8-fluoro-9-[3-((Z/E)-methoxyimino)-pyrrolidine-1-yl]-3-methyl-6-oxo-2,3-dihydro-6-H-1-oxa-3,3a-diaza-phenalene-5-carboxylic acid,    8-fluoro-9-[3-(aminomethyl)-4-methoxyimino-pyrrolidine-1-yl]-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylic acid,    8-fluoro-3-methyl-6-oxo-9-[(R)-3-(thiazol-2-ylamino)-pyrrolidine-1-yl]-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylic acid,    8-fluoro-3-methyl-6-oxo-9-[(S)-3-(2,2,2-trifluoro-acetylamino)-pyrrolidine-1-yl]-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylic acid,    9-((S)-4-amino-3,3-dimethyl-pyrrolidine-1-yl)-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H- oxa-3,3a-diaza-phenalene-5-carboxylic acid, as well as their salts.A subject of the invention is also the pharmaceutical compositions containing, as active ingredient, at least one of the medicaments according to the invention as defined above.
These compositions can be administered by oral, rectal, parenteral, in particular intramuscular route, by respiratory route or by local route in topical application to the skin and mucous membranes. The compositions according to the invention can be solid or liquid and be present in the pharmaceutical forms commonly used in human medicine, such as for example, plain or sugar-coated tablets, gelatin capsules, granules, suppositories, injectable preparations, ointments, creams, gels; they are prepared according to the customary methods. The active ingredient/s can be incorporated in same, using excipients which are customarily used in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fatty substances of animal or vegetable origin, paraffin derivatives, glycols, various wetting agents, dispersants or emulsifiers, preservatives. These compositions can in particular be present in the form of a powder intended to be dissolved extemporaneously in an appropriate vehicle, for example, non-pyrogenic sterile water. The dose administered varies according to the condition treated, the patient in question, the administration route and the product envisaged. It can, for example, be comprised between 0.25 g and 10 g per day, by oral route in humans, with the product described in Example 1 or also comprised between 0.25 g and 10 g per day by intramuscular or intravenous route.